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Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy
Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone’s adverse effects on prostate have inspired efforts to develop strategies that selectively increas...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331775/ https://www.ncbi.nlm.nih.gov/pubmed/24305501 http://dx.doi.org/10.1111/acel.12174 |
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author | Jasuja, Ravi Costello, James C Singh, Rajan Gupta, Vandana Spina, Catherine S Toraldo, Gianluca Jang, Hyeran Li, Hu Serra, Carlo Guo, Wen Chauhan, Pratibha Narula, Navjot S Guarneri, Tyler Ergun, Ayla Travison, Thomas G Collins, James J Bhasin, Shalender |
author_facet | Jasuja, Ravi Costello, James C Singh, Rajan Gupta, Vandana Spina, Catherine S Toraldo, Gianluca Jang, Hyeran Li, Hu Serra, Carlo Guo, Wen Chauhan, Pratibha Narula, Navjot S Guarneri, Tyler Ergun, Ayla Travison, Thomas G Collins, James J Bhasin, Shalender |
author_sort | Jasuja, Ravi |
collection | PubMed |
description | Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone’s adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone’s promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone’s effects on prostate, but did not affect testosterone’s anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy. |
format | Online Article Text |
id | pubmed-4331775 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-43317752015-02-19 Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy Jasuja, Ravi Costello, James C Singh, Rajan Gupta, Vandana Spina, Catherine S Toraldo, Gianluca Jang, Hyeran Li, Hu Serra, Carlo Guo, Wen Chauhan, Pratibha Narula, Navjot S Guarneri, Tyler Ergun, Ayla Travison, Thomas G Collins, James J Bhasin, Shalender Aging Cell Original Articles Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone’s adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone’s promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone’s effects on prostate, but did not affect testosterone’s anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy. BlackWell Publishing Ltd 2014-04 2013-12-04 /pmc/articles/PMC4331775/ /pubmed/24305501 http://dx.doi.org/10.1111/acel.12174 Text en © 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Jasuja, Ravi Costello, James C Singh, Rajan Gupta, Vandana Spina, Catherine S Toraldo, Gianluca Jang, Hyeran Li, Hu Serra, Carlo Guo, Wen Chauhan, Pratibha Narula, Navjot S Guarneri, Tyler Ergun, Ayla Travison, Thomas G Collins, James J Bhasin, Shalender Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy |
title | Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy |
title_full | Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy |
title_fullStr | Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy |
title_full_unstemmed | Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy |
title_short | Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy |
title_sort | combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331775/ https://www.ncbi.nlm.nih.gov/pubmed/24305501 http://dx.doi.org/10.1111/acel.12174 |
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